(+)-Hydroxyrisperidone compositions and methods

ABSTRACT

Methods and compositions utilizing a compound represented by Formula III,                    
     wherein R is chosen from —OH, —P(O)(OH) 2  and —SO 3 H, or pharmaceutically acceptable salts thereof, for the treatment of psychoses in humans are disclosed. The compounds of the present invention exhibit fewer side effects than risperidone, a lessened liability toward drug-drug interactions than risperidone and a more predictable dosing regimen than risperidone. The compounds of the invention are also useful for the treatment of emesis and withdrawal syndromes.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a §371 filing of International ApplicationPCT/US99/10426, filed May 13, 1999, and claims priority from U.S.Provisional Application 60/085,899 filed May 18, 1998 and No. 60/113,117filed Dec. 21, 1998. The entire disclosures of the earlier applicationsare incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to compositions of matter containing(+)-hydroxyrisperidone. The invention also relates to methods oftreating and preventing psychoses, emesis and symptoms of withdrawalfrom alcohol and nicotine.

BACKGROUND OF THE INVENTION

Risperidone I is an orally active, potent antipsychotic agent,commercially available in the form of Risperidal® tablets and oralsolution from Janssen Pharmaceutica.

The C_(max) of risperidone in humans is at about 3 to 9 hours after oraladministration, and the serum half-life is about 2 to 22 hours; both ofthese parameters are highly variable, depending on the subject's age,liver function, and CYP 2D6 phenotype, as will be discussed below. Themajor metabolite in human serum is 9-hydroxyrisperidone II (hereinafter,“hydroxyrisperidone”).

The hydroxylation of risperidone to its active metabolite,hydroxyrisperidone, is catalyzed in vivo by the hepatic cytochrome P450ene, CYP2D6, an enzyme that is involved in the metabolism of numerousother drugs, including tricyclic antidepressants and selective serotoninreuptake inhibitors. CYP2D6 is polymorphically expressed in the humanpopulation, and the mutant allele constitutes the recessive trait.Homozygous carriers of the mutation completely lack CYP2D6 and arereferred to as poor metabolizers (PM's); persons homozygous for the“normal” allele are extensive metabolizers (EM's); heterozygotes appearto be intermediate in metabolic capacity.

It would be desirable to find a compound that has the advantages ofrisperidone while providing a more predictable dosage regimen in thepatient population and decreasing the chances for drug-druginteractions.

Risperidone is known to give rise to several side effects, and inparticular, to extrapyramidal effects such as tardive dyskinesia. Themost frequently observed adverse reactions include orthostatichypotension and dizziness, drowsiness, palpitations, weight gain,erectile dysfunction, and a significant increase in rashes and rhinitis.

The following adverse events have been reported in risperidone-treatedpatients:

Psychiatric disorders—insomnia, agitation, anxiety, somnolence,aggressive reaction, increased dream activity, diminished desire,nervousness, depression, apathy, catatonic reaction, euphoria, increasedlibido, amnesia, emotional lability, nightmares, delirium, withdrawalsyndrome, yawning.

Central and Peripheral Nervous system disorders—extrapyramidal symptoms(including tremor, dystonia, hypokinesia, hypertonia, hyperkinesia,oculogyric crisis, ataxia, abnormal gait, involuntary musclecontractions, hyporeflexia, akathisia, increased sleep duration,dysarthria, vertigo, stupor, paraesthesia, confusion, aphasia,cholinergic syndrome, hypoesthesia, tongue paralysis, leg cramps,torticollis, hypotonia, coma, migraine, hyperreflexia andchoreoathetosis.

Gastrointestinal system disorders—constipation, nausea, dyspepsia,vomiting abdominal pain, increased salivation, anorexia, toothache,reduced salivation, flatulence, diarrhea, increased appetite,stomatitis, melena, dysphagia,. hemorrhoids, gastritis, fecalincontinence, eructation, gastroesophageal reflux, gastroenteritis,esophagitis, tongue discoloration, cholelithiasis, tongue edema,diverticulitis, gingivitis, discolored feces, GI hemorrhage, hematemesis

Body as a whole/General disorders—back pain, chest pain, fever, fatigue,edema, rigors, malaise, influenza-like symptoms, pallor, enlargedabdomen, allergic reaction, ascites, sarcoidosis, flushing

Respiratory system—rhinitis, coughing, sinusitis, pharyngitis, dyspnea,hyperventilation, bronchospasm, pneumonia, stridor, asthma, increasedsputum, aspiration

Dermatological—rash, dry skin, seborrhea, increased pigmentation,photosensitivity, increased sweating, acne, decreased sweating,alopecia, hyperkeratosis, pruritus, skin exfoliation, bullous eruption,skin ulceration, aggravated psoriasis, furunculosis, verruca, dermatitislichenoid, hypertrichosis, genital pruritus, and urticaria.

Vision Disorders—abnormal accommodation, xerophthalmia, diplopia, eyepain, blepharitis, photopsia, photophobia, and abnormal lacriniation.

Metabolic and Nutritional Disorders—hyponatremia, weight increase,creatine phosphokinase increase, thirst, weight decrease, diabetesmellitus, decreased serum iron, cachexia, dehydration, hypokalemia,hypoproteinemia, hyperphosphatemia, hypertriglyceridemia, hyperuricemia,and hypoglycemia.

Urinary System Disorders—polyuria/polydipsia, urinary incontinence,hematuria, dysuria, urinary retention, cystitis, and renalinsufficiency.

Musculo-Skeletal Disorders—arthralgia, myalgia, arthrosis, synostosis,bursitis, arthritis, and skeletal pain.

Reproductive Disorders—(Female) menorrhagia, orgastic dysfiinction, dryvagina, nonpuerperal lactation, amenorrhea, female breast pain,leukorrhea, vaginal hemorrhage, mastitis, dysmenorrhea, femal perinealpain, and intermenstrual bleeding; (Male) erectile dysfinction andejaculation failure.

Liver and Biliary System Disorders—increased SGOT, increased SGPT,hepatic failure, cholestatic hepatitis, cholecystitis, cholelithiasis,hepatitis, and hepatocellular damage.

Endocrine Disorders—gynecomastia, male breast pain, and antidiuretichormone disorder.

White Cell and Resistance Disorders—leukocytosis, lymphadenopathy,leucopenia, and Pelger-Huet anomaly.

Red Blood Cell Disorders—anemia, hypochromic anemia, and normocyticanemia.

Platelet, Bleeding and Clotting Disorders—epistaxis, purpura,hemorrhage, superficial phlebitis, thrombophlebitis, andthrombocytopenia.

Hearing and Vestibular Disorders—tinnitus, hyperacusis, and decreasedhearing.

Cardiovascular—tachycardia, orthostatic hypotension, palpitation,hypertension, AV block, myocardial infarction, ventricular tachycardia,angina pectoris, premature atrial contractions, T wave inversions,ventricular extrasystoles, ST depression, myocarditis, angioedema,atrial fibrillation, pulmonary embolism and cardiopulmonary arrest.

Risperidone and hydroxyrisperidone have also been implicated in aprolongation of QT interval, a condition associated with torsades depointes, a life-threatening arrhythmia.

Accordingly, an antipsvchotic having the efficacy of risperidone, butcausing fewer side effects, would be desirable.

SUMMARY OF THE INVENTION

Compounds used in the methods and compositions of the present inventionare represented by Formula III,

wherein R is chosen from —OH, —P(O)(OH)₂ and —SO₃H, or apharmaceutically acceptable salt thereof. The compounds possess potentactivity in the treatment of psychotic disorders (e.g., schizophrenia)and other conditions, including those that would benefit from anantidiarrheal, an inhibitor of gastro-esophageal reflux and/or anantiemetic, especially in cancer patients receiving chemotherapy andradiation. Compounds of Formula III may also be used in combatingautism, hypertension, vascular disorders, obesity, and the withdrawalsymptoms associated with cessation of drining and smoking. Compounds ofFormula III provide a more predictable dosage regimen in the patientpopulation and decrease the chances for drug-drug interactions byavoiding oxidative metabolism for which the cytochrome P450 2D6 enzymesystem is required.

DETAILED DESCRIPTION OF THE INVENTION

The active compounds of the present compositions and methods arerepresented by Formula III, above. The graphic representations ofracemic, ambiscalemic and scalemic or enantiomerically pure compoundsused herein are taken from Maehr, H., A Proposed New Convention forGraphic Presentation of Molecular Geometry and Topography, J. Chem. Ed.,62:114-120 (1985): wedge outlines and dotted or broken lines denoteenantiomerically pure compounds of indeterminate absolute configuration.Formula III thus represents whichever of the pure enantiomers of thatpair that has a positive rotation at the D-line of sodium.

Throughout this application, various references are referred to, often,although not always, within parentheses or square brackets. Thedisclosures of all of these publications (including patents) in theirentireties are hereby incorporated by reference as if written herein.The registry number of racemic hydroxyrisperidone is 144598-75-4.

Compounds of Formula III possess a center of asymmetry at the carbon towhich R is attached (C-9), giving rise to two enantiomers. The term“substantially free of its (−) stereoisomer” as used herein means that acomposition contains at least 90% by weight of the (+) stereoisomer ofthe Formula III compound and 10% by weight or less of the (−)stereoisomer of the compound. In a more preferred embodiment the term“substantially free of the (−) isomer” means that the compositioncontains at least 99% by weight of the (+) stereoisomer of the FormulaIII compound and 1% by weight or less of the (−) stereoisomer of thecompound. These percentages are based upon the total amount of theFormula III compound present in the composition. The terms“substantially optically pure (+) isomer of a compound of Formula III”and “optically pure (+) isomer of a compound of Formula III” are alsoencompassed by the above-described amounts.

The term “adverse effects” includes, but is not limited to, prolonged QTeffect, extrapyramidal effects such as tardive dyskinesia, orthostatichypotension and dizziness, drowsiness, palpitations, weight gain,erectile dysfunction, seizures, rashes and rhinitis. The term isintended to encompass at least all of the adverse events reported inrisperidone-treated patients as previously described herein.

The literature describes a close resemblance in the pharmacologicalprofiles of risperidone and its 9-hydroxy metabolite, and they have beenshown to exhibit similar effects. Megens and Awouters [Drug DevelopmentResearch 33:399-142 (1994)], concluded that “[a]s metabolic conversionof risperidone to 9-hydroxyrisperidone does apparently not result in anymarked change in activity profile, its major consequence seems to be aprolongation of duration of action.” van Beijsterveldt et al.[Psychopharmacology, 114:53-62 (1994)]similarly concluded that thepharmacological properties of the hydroxy metabolite are comparable tothe parent compound, “both in respect of the profile of interactionswith various neurotransmitters and its potency, activity, and onset andduration of action.”

It has now been discovered that compounds of Formula III are superioragents for treating psychoses and other disorders in that they provideeffective treatment while exhibiting fewer or less severe adverseeffects than risperidone, less potential for drug-drug interactions thanrisperidone, as well as a more predictable dosing regimen thanrisperidone. Compounds of Formula III also provide more predictableelimination and clearance in elderly patients and patients with impairedrenal function.

The present invention encompasses a method of treating psychoses, whichcomprises administering to a human in need of such therapy, an amount ofa compound of Formula III, or a pharmaceutically acceptable saltthereof, which is sufficient to alleviate the symptoms of psychosis. Thepresent invention further encompasses a method of treating diarrhea,gastro-esophageal reflux and emesis. The present invention yet furtherencompasses a method of treating autism, hypertension, vasculardisorders, obesity, and the withdrawal symptoms associated withcessation of drinking and smoking.

Preferably, the methods of the present invention are practiced byadministering a pharmaceutical composition in the form of a tablet,capsule, or liquid, comprising between about 1 and 20 mg of a compoundof Formula III.

Utilizing compounds of Formula III provides enhanced dosagepredictability and an improved therapeutic index as compared torisperidone. In particular, the compounds exhibit less variation in thepatient population between so-called extensive metabolizers and poormetabolizers than does risperidone.

The magnitude of a prophylactic or therapeutic dose of a compound ofFormula III required for the acute or chronic management of disease willvary with the severity of the condition to be treated and the route ofadministration. The dose and perhaps the dose frequency will also varyaccording to the age, body weight and response of the individualpatient. In general, the total daily dose range for the compounds ofFormula III for the conditions described herein is from about 1 mg toabout 20 mg in single or, preferably, divided doses. A preferred dailydose range is about 1 mg to about 10 mg in two divided doses. Inmanaging a particular patient, the therapy should be initiated at alower dose, perhaps at about 1 mg, and then increased up to about 10 mgor higher, depending on the patient's global response. It is furtherrecommended that children and patients over 65 years of age, as well asthose with impaired renal or hepatic function, initially receive lowdoses, and that they be titrated based on individual response(s) andblood level(s). It may be necessary to use dosages outside the indicatedranges in some cases, as will be apparent to those skilled in the art.Further, it is noted that the clinician or treating physician will knowhow and when to interrupt, adjust, or terminate therapy in conjunctionwith individual patient response. The terms “an amount sufficient totreat psychoses,” “an amount sufficient to alleviate the symptoms ofemesis,” “an amount sufficient to treat diarrhea,” and “an amountsufficient to treat withdrawal,” are encompassed by the above-describeddosage amounts and dose frequency schedule.

The relative activity, potency and specificity of compounds of FormulaIII may be determined by a pharmacological study in animals according tothe method of Nyberg et al. [Psychopharmacology, 119:345-348 (1995)].The method provides an estimate of relative activity, potency and,through a measure of specificity, an estimate of therapeutic index.Although the differential metabolism among patient populations can bedetermined by a clinical study in humans, less expensive andtime-consuming substitutes are provided by the methods of Kerr et al.[Biochem. Pharmacol., 47:1969-1979 (1994)] and Karam et al. [Drug Metab.Discos., 24:1081-1087 (1996)]. The potential for drug-drug interactionsmay be assessed clinically according to the methods of Leach et al.[Epilepsia, 37:1100-1106 (1996)] or in vitro according to the methods ofKerr et al.[supra] and Turner and Renton [Can. J. Physiol. Pharmacol.,67:582-586 (1989)].

Any suitable route of administration may be employed for providing thepatient with an effective dosage of a compound of Formula III. Suitableroutes of administration may include, for example, oral, rectal, nasal,buccal, parenteral (such as, intravenous, intrathecal, subcutaneous,intramuscular, intrastemal, intrahepatic, intralesional, intracranial,intra-articular, and intra-synovial), transdermal, and the like. Due totheir ease of administration, oral dosage forms, such as, for example,tablets, troches, dispersions, suspensions, solutions, capsules, softgelatin capsules, and the like, may be preferred.

Pharmaceutical compositions of the present invention comprise a compoundof Formula III, or a pharmaceutically acceptable salt thereof, as theactive ingredient, and may contain a pharmaceutically acceptablecarrier, as well as other therapeutic ingredients. The terms“pharmaceutically acceptable salts” and “a pharmaceutically acceptablesalt thereof” refer to salts prepared from pharmaceutically acceptablenon-toxic acids and bases. Salts of compounds of Formula III are moresoluble than either risperidone or hydroxyrisperidone and are thereforewell-suited for parenteral, and in particular, intravenousadministration.

Since the hydroxy compound of Formula III is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includingboth inorganic and organic acids. Suitable pharmaceutically acceptableacid addition salts of Formula III include, but are not limited to,acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric,ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic (mesylate),mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric,tartaric, p-toluenesulfonic, and the like. The hydrochloride, tartrateand pamoate salts are preferred salts of the hydroxy compound.

The phosphate and sulfate compounds of Formula III are acidic, andtherefore allow for the preparation of salts of bases as well asinternal salts. Suitable pharmaceutically acceptable base addition saltsinclude, but are not limited to, metallic salts made from aluminum,calcium, lithium, magnesium, potassium, sodium and zinc, as well asorganic salts made from chloroprocaine, choline,N,N′-dibenzylethylenediamine, diethanolamine, ethylenediamine, lysine,meglumine (N-methylglucamine) and procaime. The N-methylglucamine saltof the phosphate compound is a preferred compound for parenteraldosages, and in particular, for intravenous dosages.

The compositions of the present invention may comprise, but are in noway limited to, suspensions, solutions, elixirs and solid dosage forms.Carriers, such as starches, sugars, and microcrstalline cellulose,diluents, granulating agents, lubricants, binders, disintegratingagents, and the like are suitable in the case of oral solid preparations(such as, for example, powders, capsules, soft gelatin capsules,tablets, and the like). In some cases, it may be advantageous to coatoral solid dosage forms with an enteric or delayed-release coating, andsuch may be accomplished by standard aqueous or nonaqueous techniques.Oral dosage forms suitable for the methods and compositions of thepresent invention are described in U.S. Pat. Nos. 5,158,952; 5,453,425;and 5,612,346. In addition to the common dosage forms set out above, thecompositions of the present invention may also be administered bycontrolled release formulations, which are well known in the art.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented in the form of discrete units such ascapsules, cachets, soft gelatin capsules. and tablets, wherein each unitcontains a predetermined amount of the active ingredient, as a powder oras granules, or as a solution or a suspension in an aqueous liquid, anon-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquidemulsion. Such compositions may be prepared by any of the methods ofpharmacy, any of which will typically include the step of bringing intoassociation the active ingredient with a carrier that constitutes one ormore necessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product into the desired presentation.

Tablets, for example, may be prepared by compression or molding,optionally, with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine an amount of theactive ingredient in a free-flowing form such as powder or granules,optionally mixed with a binder, lubricant, inert diluent, surface activeagent or dispersing agent. Molded tablets may be made by molding in asuitable machine, a mixture of the powdered compound moistened with aninert liquid diluent. Desirably, each tablet or other presentation,contains between about 1 to 10 mg, and more desirably, between about 1to 5 mg of the active ingredient.

An enteric coating, such as the polyacrylate Eudragit L® and Eudragit S®series, may be applied, preferably with an aqueous dispersion of thecoating polymer. Tablets of other strengths may be prepared by alteringthe ratio of active ingredient to the excipients or to the final weightof the tablet.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of compounds and compositions ofthe present invention. It will be apparent to those skilled in the artthat many modifications, both to materials and methods, may be practicedwithout departing from the spirit of the invention.

Preparation of Compounds of Formula III

Compounds represented by Formula III of the present invention wherein Ris —OH may be prepared as described in U.S. Pat. No. 5,158,952. Example3 of the reference teaches a method for preparation of(rac)-hydroxyrisperidone from3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-4H-pyrido[1,2-a]pyrimidin4-oneand 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole monohydrochlorideutilizing an art-known N-aklylation reaction. Example 4 teaches aprocess for separation of the two isomers.

Compounds represented by Formula III of the present invention wherein Ris —P(O)(OH)₂ may be prepared by various methods. A first approachutilizes the same starting materials as the above-described preparationof hydroxyrisperidone and is based upon methods known in the art.3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-oneis treated with diphenyl chlorophosphate and N,N-dimethyl-4-pyridinaminein dichloromethane according to the protocol described in Example 13 ofpublished PCT patent application WO 95/19983. The diphenyl reactionproduct is then submitted to a two-step hydrolysis as described inExample 15 of that reference. The phosphate reaction product is thenmixed with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazolemonohydrochloride in accordance with the N-alkylation reaction describedin Example 3 of U.S. Pat. No. 5,158,952, whereby a compound of FormulaIII, wherein R is —P(O)(OH)₂ is obtained.

In accordance with a second method, the phosphate compound may beprepared from hydroxyrisperidone by treating the hydroxy compound with(1) iPr₂NP(OCH₂Ph), tetrazole; (2) t-BuOOH; and (3) Pd/C, H₂. Inaddition, the N-methylglucamine salt of the phosphate compound may beobtained by including N-methylglucamine in step (3).

Compounds of Formula 111 wherein R is —SO₃H may be prepared fromhydroxyrisperidone according to the method of Laiv and Goren [Carb.Res., 131 C, (1984)].

Preparation of Pharmaceutical Compositions Including a Compound ofFormula III

Preparation of 1 mg hydroxyrisperidone tablets: hydroxyrisperidone  1.00mg lactose 11.00 mg corn starch  2.85 mg microcrystalline cellulose 1.00 mg hydrogenated vegetable oil  0.15 mg Total weight per tablet16.00 mg

(+)-Hydroxyrisperidone, lactose and corn starch are mixed together,water is added, and the mixture is kneaded, then dried in vacuum at 40°C. for 16 hours, ground in a mortar and passed through a 16-mesh sieveto give granules. To this is added microcrystalline cellulose andvegetable oil, and the ingredients mixed thoroughly. The resultantmixture is made up into tablets, each weighing 16 mg, on a rotarytableting machine. Tablets of other strengths may be prepared byaltering the ratio of active ingredient to the excipients or to thefinal weight of the tablet.

What is claimed is:
 1. A method of treating psychoses which comprisesadministering to a human a therapeutically effective amount of acompound represented by Formula III,

wherein R is chosen from —P(O)(OH)₂ and —SO₃H, or a pharmaceuticallyacceptable salt thereof.
 2. A method of suppressing emesis whichcomprises administering to a human a therapeutically effective amount ofa compound represented by Formula III,

wherein R is chosen from —P(O)(OH)₂ and —SO₃H, or a pharmaceuticallyacceptable salt thereof.
 3. A method of treating withdrawal fromalcohol, nicotine or narcotic drugs which comprises administering to ahuman a therapeutically effective amount of a compound represented byFormula III,

wherein R is chosen from —P(O)(OH)₂ and —SO₃H, or a pharmaceuticallyacceptable salt thereof.
 4. The method of claim 1 wherein R is—P(O)(OH)₂.
 5. The method of claim 4 wherein the pharmaceuticallyacceptable salt thereof is the N-methylglucamine salt.
 6. The method ofclaim 5 wherein the compound is administered intravenously.
 7. Apharmaceutical composition comprising a therapeutically effective amountof a compound represented by Formula III,

wherein R is chosen from —P(O)(OH)₂ and —SO₃H, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.
 8. Apharmaceutical composition for intravenous administration according toclaim 7, wherein R is —P(O)(OH)₂ and the salt thereof is theN-methylglucamine salt.
 9. The method of claim 2 wherein R is—P(O)(OH)₂.
 10. The method of claim 9 wherein the pharmaceuticallyacceptable salt thereof is the N-methylglucamine salt.
 11. The method ofclaim 10 wherein the compound is administered intravenously.
 12. Themethod of claim 3 wherein R is —P(O)(OH)₂.
 13. The method of claim 12wherein the pharmaceutically acceptable salt thereof is theN-methylglucamine salt.
 14. The method of claim 13 wherein the compoundis administered intravenously.